USPTO Patents Application 09965135

OCT. 28. 2005 2:04PM JENKINS, W I LSON&TAYLOR

NO. 1810 P. 11

Serial No.: 09/965,135

REMARKS
L Status Summary

Claims 5, 8-17, and 22-25 are pending in the instant application. Claims 9-17
are withdrawn from consideration as being drawn to a nonelected invention, and
Claims 5, 8, and 22-25 have been examined.

Claims 5, 8, and 22-25 have been rejected under 35 U.S.C. § 103(a) as being
unpatentable over Gunzburg et al. (Nature, 364, 154-158, (1993); hereinafter
" Gunzburg "), U.S. Patent No. 5,658,775 to Gilboa (hereinafter "the 775 Patent"), and
Vile et al. (Cancer Research, 53, 962-967, (1993); hereinafter 'Vile").

Claim 5 has been amended herein to add clarifying punctuation and to more
clearly define the currently claimed subject matter by specifying that promoter
conversion occurs upon infection of a target cell. Support for the amendment can be
found in the specification as filed, particularly starting at page 6, line 1 to page 7, line
10, which describes that promoter conversion occurs when the vector enters the target
celL No new matter has been added.

Reconsideration of the application based on the amendments and remarks set
forth herein below is respectfully requested,

li Response to the Obviousness Rejection
Claims 5, 8, and 22-25 have been rejected under 35 U.S.C. § 103(a) as being
unpatentable over Gunzburg . the 775 Patent, and V|te. According to the Patent
Office, the cfaims are drawn to a recombinant replication-defective retroviral vector
capable of promoter conversion comprising a 5' LTR comprising the structure U3-R-
U5, a first coding sequence encoding a therapeutic peptide, a second sequence
encoding a peptide with Sag activity linked to a promoter active in B and/or T cells,
and a 3' LTR comprising a completely or partially deleted U3 region that comprises a
tissue-specific promoter that regulates the expression of the first coding sequenoe,
followed by R-U5. See Official Action , bottom of page 2 to the top of page 3.

The Patent Office asserts that the difference between the presently claimed
subject matter and the teachings of Gunzburg and the 775 Patent is "the tissue

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specific promoter that replaces the 3* LTR and the B and/or T cell active promoter
encoding Sag." See Official Action , page 3, The Patent Office further contends that
this deficiency is remedied by Vile, which teaches retroviral vectors that express
therapeutic genes with tissue specific promoters.

Thus, the Patent Office asserts that one of skill in the art would have been
motivated to use a tissue specific promoter to express the therapeutic gene specifically
in a tissue of interest, to express Sag specifically with a T and/or B cell specific
promoter to optimize Sag in those cells for proliferation, and that one would have been
motivated to regulate the expression of the therapeutic gene and Sag separately. The
Patent Office further asserts that one of skill in the art would have had a reasonable
expectation of success expressing a tissue specific promoter in the 3' LTR to regulate
the expression of the first coding sequence because the 775 Patent teaches
"replacing the 3* U3 region with any heterologous promoter and heterologous
sequence". See Official Action , page 3.

After careful consideration of the rejection and the Patent Office's bases
therefor, the applicants respectfully traverse the rejection and submit the following
remarks,

ILA The Combination ofGunzburo. the 775 Patent and Vile Does N ot Disclose or
Suggest a Retroviral Vector as Claimed in the Instant Application
Initially, applicants respectfully traverse the Patent Office's assertion that the
difference between the claimed vectors and the vectors of Gunzburg and the '775
Patent is the tissue specific promoter that replaces the 3' LTR and the B and/or T cell
active promoter encoding Sag. Applicants respectfully submit that claim 5 recites inter
alia a retroviral vector that is replication-defective and comprises the following
elements in 5' to 3' order

(a) a 5' LTR;

(b) a first coding sequence encoding a therapeutic polypeptide;

(c) a second coding sequence encoding a peptide with Sag activity operably
linked to a B cell and/or T cell promoter; and

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(d) a 3* LTR comprising a completely or partially deleted U3 region,
wherein said completely or partially deleted U3 region is replaced by a
polylinker sequence comprising at least one unique restriction site into which is
inserted one or more non-coding sequences selected from regulatory elements
and promoters, which, upon infection of a target cell, regulate expression of the
first coding sequence after promoter conversion.

Applicants respectfully submit that claim 5 recites a non-self-inactivating vector,
the body of which contains two coding sequences. The first coding sequence encodes
a therapeutic polypeptide and is promoterless in the vector, and the second encodes a
peptide with Sag activity that is operatively linked to a B cell- and/or T cell-specific
promoter. Thus, the instantly claimed vectors can provide both a peptide with Sag
activity to facilitate B-cell and/or T-cell proliferation and a therapeutic polypeptide.

Applicants respectfully submit that the vectors of Gunzburg and the 775 Patent
do not have this structure, and, as such, cannot provide this function. Gunzburg , for
example, discloses either the wild type MMTV retrovirus or various plasmid-based
vectors. Applicants respectfully submit that all of the viruses and vectors of Gunzburg
have complete U3 sequences, and thus do not have a 3' U3 deletion.

Applicants further respectfully submit that while the 775 Patent teaches some
vectors that have 3* U3 deletions, these vectors either do not have a polylinker
sequence comprising at least one unique restriction site into which is inserted one or
more non-coding sequences selected from regulatory elements and promoters (see
e.g., Figure 2C of the 775 Patent) or, if there is a promoter in the 3' U3 region, that
promoter is operatively linked in the vector itself to the coding sequence it is intended
to regulate.

These embodiments are exemplified by the vectors depicted in Figures 3, 4, 5B>
7A r 9, and 10. Thus, applicants respectfully submit that the vectors of the 775 Patent
do not have the structure of the instantly claimed vectors. Accordingly, the Patent
Office's assertion that the tissue-specific promoter that replaces the 3' LTR and the B
and/or T cell active promoter encoding Sag is the only difference between the claimed

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vectors and the vectors cited in the Gunzburg and 775 Patent is believed to be
inaccurate.

Furthermore, applicants respectfully submit that the Patent Office must consider
not only the elements that the claimed vectors and the vectors of the Gunzburg
reference and the 775 Patent might share, but also how these elements are arranged
in the vectors, the purposes of these elements in the vectors, and also what additional
components the vectors of the cited references contain. Stated another way,
applicants respectfully submit that the Patent Office must take the teachings of the
cited references as a whole, and as such it is improper for the Patent Office to pick
and choose only those claim elements that appear to be disclosed in the cited
references while neglecting to consider the clear structural differences between the
claimed vectors and the vectors disclosed in the cited references.

For example, applicants respectfully submit that only the 775 Patent teaches
any vectors with 3' U3 deletions, and in each case where there is a 3' U3 deletion, this
deletion is either maintained in the vector or is the site for cloning a minigene (/.e., a
promoter operatively linked to a coding sequence). This is in contrast to the vectors of
claim 5, which recite a 3' U3 deletion which is replaced by a potylinker into which a
regulatory element or promoter only has been cloned.

In summary, applicants respectfully submit that the Patent Office's assertion
that the difference between the claimed vectors and the vectors disclosed in the cited
references is the tissue specific promoter that replaces the 3' LTR and the B and/or T
cell active promoter is not supported by close scrutiny of the Gunzburg reference and
the 775 Patent. Thus, applicants respectfully submit that this assertion does not
support the instant rejection of claims 5, 8, and 22-25 under 35 US.C, § 103(a).

In response to the applicants' arguments made in the amendment submitted
December 13, 2004, the Patent Office asserts the following:

The insertion of a functioning promoter (as applicant states would
normally be present) at this defective site ensures expression of a
heterologous gene upstream of the body of the vector after the virus is
reverse transcribed. The replacement of the wild type promoter for a
promoter that is more specific to the heterologous gene insert would
have been prima facie obvious to one of ordinary skill in the art at the

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time the invention was made to restore normal virus replication, control
the amount of gene expression and ensure that the gene of interest is
only expressed in specifically targeted sites, as evidenced by the
teachings of Vile etal .

Official Action at page 4.

Applicants respectfully traverse these assertions on several bases. First, the
Patent Office asserts that "insertion of a functioning promoter... at this defective site
ensures expression of a heterologous gene upstream of the body of the vector once
the virus is reverse transcribed" (Official Action at page 4; emphasis added).
Applicants respectfully submit that "expression of a heterologous gene upstream of the
body of the vector" is not what is being claimed in the instant application. Applicants
respectfully submit that claim 5 recites a retroviral vector wherein the regulatory
elements and/or promoter express a heterologous gene present within the body of the
vector after promoter conversion.

Applicants further respectfully submit that there is no disclosure in the 775
Patent, Gunzburq , and/or Vile of vectors that include (1) a 3' U3 deletion; (2) a
polylinker sequence comprising at least one unique restriction site into which is
inserted one or more non-coding sequences selected from regulatory elements and
promoters cloned into the 3' U3 deletion; and (3) a coding sequence present within the
body of the vector that comes under the transcriptional control of the one or more non-
coding sequences after promoter conversion.

Thus, applicants respectfully submit that even assuming arguendo that the '775
Patent teaches a heterologous promoter cloned into a 3' U3 deletion, this promoter
must always be operatively linked to a coding sequence in the vector , or a SIN vector
will not result. Since the only vectors disclosed in the '775 Patent that contain 3' U3
deletions are SIN vectors, applicants respectfully submit that the disclosure of the 775
Patent teaches against cloning regulatory sequences and/or a promoter into the 3' U3
deletion and using the regulatory sequences and/or promoter to regulate expression of
a coding sequence present within the body of the vector.

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Stated another way, applicants respectfully submit that if regulatory sequences
and/or a promoter are cloned into a 3' U3 deletion without being operably linked to a
coding sequence ( as is the case with the vectors of claim 5 of the instant application,
then the vector will not be a SIN vector Accordingly, applicants respectfully submit
that the 775 Patent cannot be read to suggest the structure of the 3' LTR that is
recited in the instant claims, and further respectfully submit that the combination of
Gunzburg and the 775 Patent cannot be read to suggest such a structure.

Applicants respectfully submit that VQe does not cure this deficiency. Even
assuming arguendo that VHe discloses retroviral vectors that express therapeutic
genes from tissue-specific promoters, it does not overcome the lack of a teaching or
suggestion in the combination of Gunzburg and the 775 Patent concerning the
production of a retroviral vector with a heterologous promoter cloned into the 3' U3
region that can be used to regulate the expression of a therapeutic gene positioned in
the body of the vector.

Therefore, applicants respectfully submit that the combination of Gunzburg , the
775 Patent and Vile does not support a rejection of claims 5, 8, and 22-25 under 35
U.S.C. § 103(a). As such, applicants respectfully request that the instant rejection be
withdrawn and the claims allowed at this time.

I LB. The Combination of Gunzburg the '775 Patent and Vile Does Not D isclose or
Suggest a Retroviral Vector with Two Coding Sequences in the Body of the Vector
In addition to the deficiency discussed immediately hereinabove, applicants
respectfully submit that the combination of Gunzburg . the 775 Patent, and Vile does
not disclose or suggest a retroviral vector with a promoterless therapeutic gene coding
sequence and a Sag peptide coding sequence operatively linked to a B and/or T ceil
specific promoter, wherein both of these coding sequences are present within the body
of the vector. The Patent Office asserts, however, that since Claim 25 of the 775
patent is specifically drawn to a vector containing "a second, non-retroviral DNA
sequence" within the body of the vector, the 775 Patent does teach a vector
comprising two coding sequences within the body of the vector.

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Applicants respectfully disagree. Applicants respectfully submit that even
though Claim 25 of the 775 Patent recites a second, non-retroviral DNA sequence
inserted in the body of the vector, this claim depends from claim 1, and that according
to Claim 1, the first coding sequence is the transcription unit inserted only into the U3
region of the 3' LTR . Since the transcription unit is present in the 3' U3 region, it is not
in the body of the yejrtor , which is the region of the vector between the LTRs .

This is elaborated in the final clause of Claim 1 of the 775 Patent, which states
that "infection of the eukaryotic cell with the retroviral vector results in the transcription
unit being duplicated and appearing in both the 5' and 3' LTR of the retroviral vector".
Based on the mechanics of the reverse transcription reaction, only sequences that are
within the LTRs become duplicated, and therefore applicants respectfully submit that it
is clear that the transcription unit recited in Claim 1 is not in the body of the vector.

Accordingly, applicants respectfully submit that the 775 Patent does not
disclose two coding sequences present within the body of the vector. Further,
applicants respectfully submit that the combination of Gunzbura , the 775 Patent and
Vile does not disclose or suggest a retroviral vector with two coding sequences
present within the body of the vector, wherein, upon promoter conversion following
infection of a target cell, the expression of one of the two coding sequences is driven
by a promoter originally located in the 3' U3 region of the vector, as is recited in Claim
5 of the instant application.

il.C. The Constructs Disclosed in the 775 Patent Do Not Have Sao Activity
The Patent Office further asserts that the construct of the 775 Patent "also has
Sag activity since Gunzburg et a/ , teach that Sag is present in the U3 region of the 5'
MMTV LTR, see Figure 1a/ See Official Action, page 5. Applicants respectfully
disagree. Applicants respectfully submit that the 775 Patent lists a number of
retroviruses upon which the vectors described therein can be based. See 775 Patent,
column 8, lines 51-58. The '775 Patent discloses the use of the avian sarcoma virus
(AvSV), the murine sarcoma virus (MuSV), and murine leukemia viruses such as the
mouse Maloney leukemia virus (M-MuLV). None of the vectors described in the 775

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Patent contain a 5' mouse mammary tumour virus (MMTV) LTR, the LTR described in
Gunzburq as containing the novel B cell specific promoter and the coding sequences
for Sag in the U3 region of its LTR. Therefore, applicants respectfully submit that the
775 Patent could not be read in view of Gunzburq to suggest that the constructs of the
775 Patent have Sag activity. Further, Vjle does not provide any suggestion that any
of the elements of the vector constructs of the 775 Patent would encode a peptide
with Sag activity.

ILD. There is No Motivation to Combine Hie References
Additionally, in order to establish a prima facie case of obviousness, there must
be some motivation to combine the references as suggested by the Patent Office.
According to the Patent Office, one of ordinary skill in the art would have been
motivated to (a) express the heterologous therapeutic gene with a tissue specific
promoter to express a gene of interest in a tissue of interest more specifically; (b)
express Sag with a T and/or B cell specific promoter to optimize Sag expression in
those cells for proliferation; and (c) express Sag from a T and/or B cell specific
promoter to regulate its expression separately for the therapeutic gene.

Applicants respectfully submit that the Patent Office offers no support for the
assertions presented hereinabove. Rather, the Patent Office presents only conclusory
statements concerning these asserted motivations. As such, it appears that the
motivations presented amount to no more than what one of ordinary skill in the art
could have done . Applicants respectfully submit that according to MPEP 2143.01 , the
fact that references ran be combined or modified is not sufficient to establish prima
facie obviousness,

Indeed, applicants respectfully submit that the Patent Office has employed an
impermissible hindsight reconstruction of the references to arrive at the instant
rejection, and as such, has not presented a prima facie case of obviousness of claim 5
over the combination of Gunzburq , the 775 Patent, and Vile .

And finally, applicants respectfully submit that there can be no motivation to
combine Gunzburq, the 775 Patent, and Vile because the 775 Patent discloses self-

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Inactivating vectors and the instantly claimed vectors are not self-in activating.
According to MPEP 2143.01, *[i]f the proposed modification or combination of the prior
art would change the principle of operation of the prior art invention being modified,
then the teachings of the references are not sufficient to render the claims prima facie
obvious" (citing In re RaW } 270 F.2d 810, 123 USPQ 349 (CCPA 1959)).

To elaborate, applicants respectfully submit that the deletion of the 3' U3
sequences in the instantly claimed vectors results in the regulatory sequences and/or
the promoter cloned into the deleted region being capable of regulating the
transcription of the therapeutic gene present within the body of the vector. This
principle, referred to in the instant specification as "promoter conversion", is a feature
of a non-self-inactivating vector. Applicants respectfully submit that bv definition , a
self-inactivating vector such as those disclosed in the 775 Patent cannot undergo
promoter conversion resulting in a coding sequence present within the body of the
vector coming under the transcriptional control of a regulatory sequence or promoter
present in the 3' U3 region. Gunzbura and Vile do not cure this deficiency.

Thus, applicants respectfully submit that the Patent Office's proposed
combination of Gunzburq, the 775 Patent, and Vj!e is proscribed by MPEP 2143.01,
and as such, does not support a prima facie case of obviousness of claim 5.

//.E. Summary

Accordingly, with respect to the instant rejection of independent Claim 5 under
35 U,S,C. § 103(a) over Gunzburg, the 775 Patent, and Vile, applicants respectfully
submit that the cited combination does not support a prima facie case of obviousness
for several reasons. First, the references do not disclose retroviral vectors that contain
partial 3' U3 deletions into which a poiylinker and a promoter and/or a regulatory
element(s) has been inserted; wherein after infection of a target cell, a coding
sequence present in the body of the vector becomes operatively linked to the promoter
and/or regulatory sequence(s), and the promoter and/or regulatory sequences then
regulate expression of the coding sequences present within the body of the vector in
said target cell. Second, the references do not provide a vector containing two coding

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sequences within the body of the vector, one encoding a therapeutic peptide and one
encoding a peptide with Sag activity. Finally, there is no motivation to combine the
cited references because one of ordinary skill in the art would not look to the 775
Patent to design a retroviral vector that is not a self-inactivating vector. Applicants
respectfully submit that it is improper to combine the cited references to arrive at the
vector described in Claim 5, because doing so would change the principle of operation
of the vector described by the 775 patent.

Thus, applicants respectfully request that the instant rejection of Claim 5 under
35 U.S.C. § 103(a) over the combination of Gunzburq . the 775 Patent, and VHe be
withdrawn, Claims 8 and 22-25 depend from claim 5, and, thus, claims 8 and 22-25
also are believed to be patentably distinguished over the cited combination.
Therefore, applicants respectfully submit that claims 5, 8, and 22-25 are in condition
for allowance, and respectfully solicit a Notice of Allowance to that effect.

CONCLUSIONS

In light of the above amendments and remarks, applicants respectfully submit
that claims 5, 8, and 22-25 are in condition for allowance at this time, and respectfully
solicit a Notice of Allowance to that effect.

If any small matter should remain outstanding after the Patent Examiner has
had an opportunity to review the above Remarks, the Patent Examiner is respectfully
requested to telephone the undersigned patent attorney in order to resolve these
matters and avoid the issuance of another Official Action.

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DEPOSIT ACCOUNT
The Commissioner is hereby authorized to charge any fees associated with the
filing of this correspondence to Deposit Account No. 50-0426 .

Respectfully submitted,

JENKINS, WILSON & TAYLOR, P.A.

Date: IV WFU>6h, By:

Aries A. Taylor, Jr.
Registration No. 39,395

1406/206 AAT/CPP/ALO/acy
Customer No: 25297

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